Hematopoietic Receptor Family

The functional high-affinity receptors for IL-3, IL-5, and GM-CSF are heterodimeric receptors consisting of a cytokine-specific a subunit and the common beta subunit. beta-c, which is shared by the three cytokines. In the mouse, the IL-3-specific beta-IL3 subunit. homologous to beta-c, is present and forms a high-affinity receptor only with the IL-3R-alfa. These subunits are members of the type I cytokine receptor family.As the beta subunits play a major role in signaling, the three cytokines exhibit similar biological functions on the same target cells. The JAK2 tyrosine kinase is associated with both beta subunits and is activated upon cytokine stimulation. The membrane-proximal region of beta-c is responsible for the activation of JAK2 and STAT5 as well as induction of c-myc. The signals induced by this region are required for cell cycle progression and DNA synthesis. The activation of the Ras pathway requires the distal region of beta-c and is involved in suppression of apoptosis. As IL-3. IL-5, and GM-CSF are produced mainly from activated T cells and mast cells, it has been hypothesized that these cytokines play a major role in inductive hema-topoiesis associated with immune and inflammatory reactions. However, mice lacking the entire functions of IL-3. IL-5. and GM-CSF are viable and no significant defects other than a reduced level of eosinophils and some defects in mast cell development were found, even in mice infected with bacteria and parasites. Thus, there appears to be a compensatory mechanism to overcome any defect in the three cytokines.